DESCRIPTION (APPLICANT'S ABSTRACT): Glucosamine is a nutritional supplement commonly used for the relief of joint pain. However, it is not subject to FDA regulation and its long-term safety is unknown. Glucosamine is used in the synthesis of glycosaminoglycan chains on proteoglycans. Vascular proteoglycans play a key role in atherogenesis due to their retention of atherogenic lipoproteins in the arterial wall. Thus, glucosamine use could potentially be atherogenic. Previous studies have yielded conflicting results with respect to the atherogenic potential of glucosamine. Some studies have suggested that glucosamine may have pro=atherogenic effects, while others suggest an anti-atherogenic effect. This grant proposes to investigate the role of glucosamine in vascular . proteoglycan biosynthesis and lipoprotein retention in vitro, andin vivo. The major hypothesis of this grant is that glucosamine supplementation will result in altered proteoglycan synthesis by vascular-smooth muscle cells, which will in turn result in an altered propensity to atherosclerosis. Depending on the nature of these altered vascular proteoglycans, glucosamine supplementation could either enhance susceptibility to, or protect against, atherosclerosis. This grant proposes to study the effect of glucosamine supplementation on the structure and function of proteoglycans synthesized by monkey aortic smooth muscle cells in vitro. Studies will be performed to determine the effect on-degree of sulfation, size, and ratio of classes of proteoglycans synthesized by vascular smooth muscle cells, and the retention of atherogenic lipoproteins by these altered proteoglycans. In addition, this grant proposes to address the effect of glucosamine supplementation in vivo. LDL receptor deficient mice, a mouse model of atherosclerosis that has a human-like lipoprotein profile, will be supplemented with oral glucosamine, and the extent of atherosclerotic lesions will be determined. The findings from the proposed study should provide important insights into the potential effects of glucosamine supplementation on atherosclerotic cardiovascular disease.